Alzheimer's disease (AD) is characterized by the presence of both beta-amyloid plaques and neurofibrillary tangles in brain. Increasing evidence favors the generation and deposition of amyloid b-protein (Ab) in plaques as an early and possibly primary event in the pathogenesis of AD. Ab is derived from the amyloid precursor protein (APP) by multiple proteolytic cleavages. The pathways leading to the generation and release of Ab are now being defined, pointing to both the secretory and endocytic pathways as sites of Ab production. We have proposed that the endocytic processing of APP is a major pathway for the generation and release of Ab from wild type APP. In this continuing study on the pathways and mechanisms that are responsible for Ab generation, we will focus on the role of the low-density lipoprotein receptor-related protein (LRP) on APP processing. Our preliminary results have led to the working hypothesis that the interaction of APP and LRP via the respective cytosolic regions, either directly or indirectly, regulates APP processing andAb production. We found that loss of LRP results in a wide range of perturbations in APP processing,including APP turnover, levels of APP C-terminal fragments, APP secretion, APP internalization, and Ab production, more extensive than have been described by any other APP interacting protein. Further studies showed that a small domain in the cytoplasmic tail of LRP is necessary and sufficient to mediate these effects. Three Specific Aims are proposed in the next granting period to test the hypothesis that LRP is a majorregulator of APP processing. The first Aim will determine the specific LRP sequences and define the cellular sites that are critical for LRP dependent APP processing. The second Aim will explore the mechanism of action of LRP on APP and will integrate our findings into current models of Ab generation. The third Aim will test whether the LRP-APP interaction can be exploited in ways to reduce Ab production in cultured systems and in transgenic mouse models. Results from the proposed studies should provide significant new insights into ways in which APP processing and trafficking can be regulated, and in so doing, regulate Ab production. Moreover, the studies may provide novel approaches to reduce Ab production without inhibiting gamma secretase activity.